Is TP53 p.Arg175His (c.524G>A) pathogenic?

TP53 p.Arg175His (c.524G>A) is classified Pathogenic in TP53 (ClinVar, Expert panel, 39 submitters; last evaluated 2024-09-06). AlphaMissense: likely pathogenic (0.9857); Very rare (popmax 0.000593%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg175His (c.524G>A)?

TP53 p.Arg175His (c.524G>A) is associated with Li-Fraumeni syndrome, gastric cancer, bone osteosarcoma (ClinVar).

How common is TP53 p.Arg175His (c.524G>A) in the general population?

TP53 p.Arg175His (c.524G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Arg175His (c.524G>A)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

TP53 p.Arg175His

c.524G>A · rs28934578 · VCV12374

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 39 submitters

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic ✓ concordant with ClinVar
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -15.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,032 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,062 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

ClinGen expert panel — TP53 VCEP

Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PP1_Moderate PS3 PS4_Moderate PM1 PP3

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Cancer	MDM2 Inhibitor AMGMDS3	D	Resistance
		D	Dominant Negative
Stomach Carcinoma	EAP Protocol	C	Sensitivity/Response
Breast Cancer	Doxorubicin	D	Sensitivity/Response
Breast Cancer		B	Poor Outcome
Cancer	MDM2 Inhibitor AMGMDS3	D	Resistance
		D	Loss of Function
		D	Dominant Negative

Variant & gene context

Gene: TP53
Protein: p.Arg175His
Coding: c.524G>A
MANE Select: NM_000546
dbSNP: rs28934578
Type: single nucleotide variant
Location: chr17:7675088 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 175: a DNA-binding region; the 'interaction with axin1' region; an α-helix; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation; reduces interaction with znf385a); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer bone osteosarcoma exocrine pancreatic carcinoma colorectal cancer hepatocellular carcinoma esophageal cancer adrenocortical carcinoma, hereditary choroid plexus papilloma head and neck squamous cell carcinoma basal cell carcinoma, susceptibility to, 7 hereditary neoplastic syndrome nasopharyngeal carcinoma hereditary breast carcinoma ovarian neoplasm lip and oral cavity carcinoma glioma susceptibility 1 bone marrow failure syndrome 5

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Arg175Gly Pathogenic ★★★ same residue
TP53 p.Arg175Leu Likely pathogenic ★★★ same residue
TP53 p.Arg175Cys Uncertain significance ★★★ ⚠ same residue
TP53 p.Arg175= Benign/Likely benign ★★ same residue
TP53 p.Arg175Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A Pathogenic ★★★ same condition
TP53 c.97-1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tp53-p-arg175his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown